Changes in the 7th edition of the AJCC TNM
classification and recommendations for pathologic analysis of lacrimal
gland tumors.

Abstract:

* In our recent work to update the American Joint Committee on
Cancer's AJCC Cancer Staging Manual, we brought the staging system
in line with that of salivary gland malignancies to better describe the
range of these tumors. In addition, we have suggested that information
be collected on biomarkers and clinical and histologic data points. This
revised staging, along with careful histologic analysis and patient
follow-up, may provide information that helps develop more targeted
management for these lesions.

The multi-institutional study coordinated by the University of
British Columbia (Vancouver, Canada), and published in the special issue
of the Archives of Ophthalmology, (1) emphasizes the lack of consistent
data collection, both clinical and pathologic, for complete description
and documentation of lacrimal epithelial tumors.

Because of insufficient information in updating to the 7th edition
of the TNM classification system for lacrimal gland tumors, we chose to
bring the classification in line with that of the more numerous salivary
gland malignancies (Table 1). (2) The TNM classification for salivary
gland tumors shows good separation in outcome from T1 to T4. (3)
Consequently, we have adjusted the sizes for lacrimal gland tumors to
reflect those in the salivary glands for T1 to T3 (Figures 1 through 3).
In addition, we have increased the number of histologic categories from
10 to 17 and divided them into low and high grade, on the basis of the
World Health Organization classification of salivary gland tumors, as
essentially all of these tumors have been described in the lacrimal
gland, even if only in single case reports (Table 2). (4,5) We have
requested that the classification NOT be used for malignancies of the
lacrimal sac and drainage apparatus, as tumors of this site have a much
different clinical course and pathologic spectrum. Finally, we have
divided T4 into 3 categories to provide for greater distinction between
periosteal and bony involvement and have created a category of
unresectable disease (Figure 4).

Recently, Ahmad et al (6) have provided preliminary evidence that
the American Joint Committee on Cancer (AJCC) classification does
correlate with outcome in adenoid cystic carcinoma (ACC) of the lacrimal
gland.

A new feature of the 7th edition of the AJCC Cancer Staging Manual
(2) will be the ability to collect data on biomarkers and additional
data points in an attempt to extend the classification system beyond
solely an anatomic-based one. There is little evidence for the
application of biomarkers in salivary or lacrimal tumors, so we have
chosen to request data on proliferative index and nuclear staining for
the tumor suppressor gene NM23, as these have shown some evidence of
prognostic value in limited studies. (7,8) Regarding additional data
points, we have separated that information into clinical and histologic.
Clinical data points include information about the type of surgery
performed and whether preoperative or postoperative chemotherapy and/or
postoperative radiotherapy were given. This is in an attempt to
determine the most appropriate method of treatment for high-stage tumors
as radical exenteration may not be the treatment of choice. Pathologic
data points include the largest diameter of the tumor, presence of
basaloid morphology in adenoid cystic carcinomas, presence of perineural
invasion, and extent of invasion beyond the capsule in carcinomas ex
pleomorphic adenoma.

Clinical staging should include a complete history (with emphasis
on duration of symptoms, change in tempo of symptoms, and pain or
dysesthesia) and physical examination (including globe displacement or
distortion, palpation, and sensory and motor examination). Both computed
tomographic imaging, which is better for bone, and magnetic resonance
imaging, which is better for soft tissue, of the orbit should be
performed to provide critical diagnostic and staging data. Orbital
imaging should evaluate size, shape, extent, and invasion of adjacent
structures including bone, marrow spaces, skull base, and periorbital
areas. To stage the extent of disease, evaluation of the cervical lymph
nodes, lungs, and bone should be included.

Ever since Godtfredsen (9) first differentiated benign from
malignant lacrimal tumors more than 50 years ago, we have continually
improved our ability to distinguish varieties of these tumors, which may
have differing biologic behavior that need to be incorporated into the
pathologic analysis. Benign pleomorphic adenomas can harbor areas of
cellular atypia without implying malignancy or can show anaplasia,
necrosis, and increased mitotic activity indicating frank carcinoma.
This appears to be more likely in tumors with myoepithelial cell
predominance or with significant hyalinization. (1) Therefore,
pleomorphic adenomas showing these features should be well sampled. If
an area of carcinoma ex pleomorphic adenoma (CEPA) is discovered, it is
crucial to determine whether it extends beyond the limits of the
capsule. Noninvasive CEPA and pleomorphic adenoma with atypia are
unlikely to cause future morbidity if excised without breach of the
capsule. In contrast, invasive CEPA carries a prognosis as grim as that
of primary carcinoma when it has extended significantly beyond the
capsule. (1,4)

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Thorough histologic examination of ACC is similarly important and
estimation of the proportions of tubular, cribriform, and solid
components throughout has prognostic significance, with the presence of
any solid component and absence of any cribriform areas portending the
worst prognosis. (4,5) Involvement of the margins as well as perineural
invasion should also be explicitly stated. Furthermore, ACC may rarely
harbor areas of dedifferentiation, which may denote more aggressive
potential. (10)

The pathologist must consider rare entities such as basal cell
adenocarcinoma and polymorphous low-grade adenocarcinoma when
considering a diagnosis of lacrimal carcinoma, since each of these is
associated with a considerably better prognosis than ACC. Additional
case reports or series, particularly multi-institutional prospective
studies with agreed-upon criterion and staging of unusual lacrimal gland
tumors, will allow for further evaluation of the management of these
more rare entities.

The full extent of a lacrimal gland malignancy may be
underestimated in a typical excisional biopsy by lateral orbitotomy. As
the lacrimal gland is adjacent to other crucial structures, wide tissue
margins are rarely obtained. Questions of perineural extension and local
bone invasion often go unanswered. Careful intraoperative inspection of
adjacent orbital bone with biopsy or removal of any suspicious areas is
warranted. Pathologic specimens should be closely examined for
perineural and vascular invasion. Any and all bone removed should be
examined pathologically for accurate staging purposes.

In view of the above, the specimen should be handled in a
particular fashion. It should be oriented, marked, and analyzed in terms
of its position in the orbit and its adjacencies in order for step
sectioning to allow for a 3-dimensional analysis of the tumor itself and
adjacent tissues. The tumor should be sampled to evaluate histologic
type, grade, size, presence of preexisting pleomorphic adenoma, and
surgical margins (including the periosteum). Perineural spread, most
characteristic of ACC, can result in a clinical underestimation of the
true anatomic extent of the disease.

When handling exenteration specimens for lacrimal gland neoplasms,
we recommend that the specimen be handled en bloc. The superior and
inferior orbital margins should be inked with different colors. The
specimen should be sectioned parasagitally in from 5 to 7 slices from
0.5 to 1 cm in thickness. As the superotemporal and posterior orbital
margins are of most interest, the temporal slice can be further
sectioned horizontally to obtain a complete perpendicular view of the
margin, rather than an en face view. (11) If adjacent bone is obtained
with en bloc excision because of sufficient spread, it should be
oriented in a standardized manner and fully examined pathologically for
evidence of involvement. Esmaeli (12) has recently shown that bone was
involved in 50% of her series of adenoid cystic carcinomas. If bone is
still attached to the specimen and is difficult to remove, the entire
specimen can be decalcified in 10% formic acid without loss of cellular
detail on histologic examination, although this process can take 2 to 3
weeks for sufficient decalcification to occur for optimal sectioning.

As both benign and malignant lacrimal tumors can recur decades
after initial excision and some of the benign tumors can undergo
malignant transformation, it is imperative to establish lifelong
follow-up for these patients. Hopefully, careful histologic analysis,
use of the 7th edition of the AJCC Cancer Staging Manual, and long-term
follow-up will allow us to develop more specific and rational management
of these difficult tumors and enable us to decrease the sometimes dismal
morbidity and mortality of lacrimal epithelial tumors.

We would like to acknowledge Bita Esmaeli, MD, James C. Fleming,
MD, Zeynel A. Karcioglu, MD, David Tse, MD, and Christian Wittekind, MD,
for reviewing the changes for the 7th edition of the AJCC Cancer Staging
Manual

We would also like to acknowledge Jack Rootman, MD, and Ms. Wilma
Chang for creating the illustrations.